Traumatic Brain Injury (TBI) is a common acquired disorder of the nervous system with a broad spectrum of severity and heterogeneity ranging from lethal penetrating injuries to closed head injury with concussion. It is estimated that approximately 1.4 million people in the US experience TBI every year caused by transportation and vehicular accidents, falls, sports injuries, gunshot wounds, and child abuse. Of these, at least 1 million are treated in emergency rooms, about 50,000 people die annually from TBI, and about 230,000 are hospitalized and survive. An additional source of TBI is related to military action abroad due to the frequency of blast injuries, which are increasingly common but survivable due to improvements in acute emergency care in contemporary combat zones. While survivability has increased, individuals who survive TBI are often left with significant cognitive and communicative disabilities, behavioral disorders such as post-traumatic stress disorder (PTSD), and long-term medical complications such as epilepsy (PTE).
The emergence of PTE and PTSD after TBI is a prototypical example of an acquired brain injury leading to adverse long-term functional consequences. PTE and PTSD may develop and progress despite long intervals after the initial injury, implying that neuronal and brain circuit plasticity initiated by the injury may contribute to development of these disorders. Neural plasticity is the capacity of neurons and neural circuits in the brain to undergo structural and functional modification in response to experience, activity, and injury. While the adult brain was once regarded as “hard-wired” with only limited capacity for adaptation, alteration, and reorganization of function, plasticity is now recognized as a fundamental property of the brain that plays a role not only in development but in learning, memory, cognition, pathological processes, and recovery of function after brain injury. Plasticity is defined as the ability of the brain to undergo changes in structure and function. Cellular processes underlying plasticity are now thought to operate at every level of biological organization in the brain, including molecular and cellular levels as well as circuits, networks, and systems. In regard to TBI, plasticity has been implicated as a potential influence on recovery of function after damage, but in addition, processes of plasticity are also hypothesized to contribute to long-term adverse consequences such as PTE, specifically during the latent period from initial injury to emergence of symptomatic seizures. Development of PTE, PTSD or other deleterious sequellae of TBI is unpredictable, even in individuals who experience TBI of apparent comparable severity and location.
Currently, TBI therapy is limited primarily to surgical treatment of the initial injury when possible and supportive general medical care. There have been long-standing and continuing efforts to develop new therapies for TBI survivors, with the goal of reducing the initial extent and progression of TBI, and preventing its long-term complications such as PTSD and PTE. Unfortunately, no efficacious therapies for TBI have been demonstrated in the art. However, a wide variety of agents have been evaluated in experimental models of TBI and in clinical trials in TBI patients, comprising more than 250 clinical trials that are underway for TBI which include studies of both marketed drugs and new chemical entities in preclinical development. Thus, there is a need in the art to develop methods and compounds for treating TBI and its consequences.